US20130030007A1 - Obesity Small Molecules - Google Patents

Obesity Small Molecules Download PDF

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US20130030007A1
US20130030007A1 US13/520,961 US201113520961A US2013030007A1 US 20130030007 A1 US20130030007 A1 US 20130030007A1 US 201113520961 A US201113520961 A US 201113520961A US 2013030007 A1 US2013030007 A1 US 2013030007A1
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cyp3a4
abcb1
jun
compound
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Josef Penninger
Andrew Pospisilik
Shane McManus
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AKRON MOLECULES GmbH
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to the field of pharmaceutical compounds and methods for the treatment of overweight and obesity.
  • the world health organization currently estimates that as of 2009 over 1 billion individuals worldwide are overweight. Almost one third of these individuals are clinically obese, markedly raising their chances of cardiovascular disease, type-2 diabetes, cancer, and stroke.
  • the regulation of body fat content in animals results from the integration of multiple nutrient, sensory, and hormonal inputs primarily at the level of the brain and adipose tissues. This integrative network is influenced not only by genetics, but also by circadian rhythm and physical and social environments. Obesity is thus, a complex, systems level disease.
  • the present invention therefore provides a method of reducing weight and/or body fat in a subject comprising the administration of a therapeutic compound selected from the compounds of table 1.
  • a therapeutic compound selected from the compounds of table 1 E.g. a therapeutic dose disclosed or approved for other therapeutic uses for each of these compounds can be used.
  • the present invention provides a method of reducing triglyceride levels, in particular LDL levels, in a subject comprising the administration of a therapeutic compound selected from the compounds of table 1.
  • the present invention provides the use of a compound of table 1 for the manufacture of a medicament for the therapeutic administration to reduce body weight and/or body fat or to treat obesity in a subject. Also provided are these compounds for use in the therapies disclosed herein. The invention is further defined by the subject matter of the claims.
  • the present invention relates to use of the following compounds for the above tratments, in particular for reducing weight and/or body fat in a subject:
  • inventive use of the compounds given herein includes the use of any pharmaceutically acceptable salt or hydrate form thereof.
  • the inventive compounds are used in the treatment of obesity, in particular severe obesity.
  • Obesity is defined as an excess of body fat.
  • Body mass index (BMI—the ratio of body weight in kg to the square of the height of an individual in m), is a useful measure of fat distribution. Importantly it allows the stratification of patient categories to identify increased risk of morbidity and mortality and the identification of suitable interventions. Furthermore it provides a firm basis for the assessment of intervention strategies.
  • Class II obesity is severe obesity and class III obesity is referred to as extreme obesity, associated with an extremely high risk of comorbidities including Type 2 diabetes mellitus; Hypertension; Dyslipidemia; Cardiovascular disease including Coronary artery disease, Stroke and Congestive heart failure; Nonalcoholic fatty liver disease (steatosis, steatohepatitis, cirrhosis); Respiratory disease including Obstructive sleep apnea, Obesity-hypoventilation syndrome, Asthma, Restrictive lung disease; Cancer; Osteoarthritis; Cholelithiasis; Gastroesophageal reflux disease; Gynecologic abnormalities including Infertility, Abnormal menses; Venous stasis; Skin problems such as Intertrigo and Cellulitis; Increased risk of complications during surgery or pregnancy; Urinary incontinence; Idiopathic intracranial hypertension (Hensrud et al., 2006).
  • the subject to be treated according to the present invention can be any non-human animal or a human.
  • the subject is a mammal, in particular preferred embodiments a human.
  • obesity diseases associated with obesity, e.g. diabetes
  • a prophylactic administration can be treated or prevented, in particular in the meaning of a prophylactic administration.
  • Preventing or “prevention” herein does not require absolute success in the sense of an absolute prevention of a heart disease but indicates a reduced risk of developing a disease, or developing a disease with reduced severity.
  • treatment shall not be construed as an absolute cure, but may also relate to amelioration of the disease or disease symptoms.
  • “About” is used to refer to certain dosages that can vary from a given value, nevertheless with the same effects as the indicated dose. In some embodiments “about” may refer to +/ ⁇ 20% or 10% of a given value.
  • the compound is administered in a dosage sufficient to treat or prevent said diseases.
  • Administration can e.g. be a single dose administration or a successive or repeated administration, e.g. twice a day, daily or in an interval of at least 1 day, at least 2 days, at least 3 days, at least 1 week, preferably at least 2 weeks, at least 4 weeks, at least 8 weeks or even more preferred at least 12 weeks.
  • the compound is provided in a pharmaceutical composition or a medicament.
  • the composition or medicament may comprise a pharmaceutical carrier.
  • Pharmaceutical carrier substances serve for a better tolerance of the medicament and allow for a better solubility as well as a better bioavailability of the active substances contained in the medicament. Examples of this are emulsifiers, thickening agents, redox components, starch, alcohol solutions, polyethylene glycol or lipids.
  • a suitable pharmaceutical carrier is highly dependent on the manner of administration. For oral administrations, liquid or solid carriers may be used, for injections, liquid final compositions are required.
  • suitable vehicles can be includes such as liposomes or microsomes.
  • the medicament or the compound to be used according to the invention comprises buffer substances or tonic substances.
  • a buffer By means of a buffer, the pH of the medicament can be adjusted to physiological conditions, and moreover, pH fluctuations can be attenuated, or buffered, respectively.
  • An example thereof is a phosphate buffer.
  • Tonic substances serve for adjusting the osmolarity and may comprise ionic substances, such as, e.g., inorganic salts, such as NaCl, or also non-ionic substances, such as, e.g. glycerol or carbohydrates.
  • the inventive compound or medicament can be administered topical, enteral or parenteral, in particular preferred oral or rectal, intravenous, intraarterial, intramuscular, subcutaneous, intradermal or intraperitoneal, transdermal, transmucosal or inhalational.
  • Preferred routes of administration of the inventive agent according to the present invention are parenteral routes, preferably intraperitoneal or intravenous administration, intravenous administration being specifically preferred.
  • Intravenous administration can be performed e.g. via bolus injection or by continuous intravenous delivery over a longer time period (e.g. 30 min to 6 h, especially 1 to 3 h).
  • Further routes include oral or transdermal or subcutaneous routes. In particular preferred is oral administration.
  • parenteral routes are preferred for digestible agents, such as active proteins, peptides or siRNA.
  • the medicament or the compound to be used according to the invention can be prepared to be suitable for oral or intranasal administration.
  • These administration forms of the medicament of the present invention allow for a rapid an uncomplicated uptake of the active substances via the mucous membranes.
  • nose drops or nose sprays are suitable.
  • solid or liquid medicaments may, e.g., be taken directly or in a dissolved or diluted state, respectively.
  • the medicament or compound to be used according to the invention can be prepared for an intravenous, intra-arterial, intramuscular, intravascular, systemic, intraperitoneal or subcutaneous administration.
  • intravenous, intra-arterial, intramuscular, intravascular, systemic, intraperitoneal or subcutaneous administration e.g., injections or transfusions are suitable.
  • Administrations directly into the bloodstream have the advantage that the active substances of the medicament will be distributed in the entire body and will quickly reach the target tissue, in particular the heart muscle.
  • the compound may be administered in a effective therapeutic dose.
  • Effective doses are in the range of dosages known for these compounds for other, non-obesity related administrations.
  • a dosage can be determined by a simple test using drosophila or mouse test systems, e.g. as shown in example 3.
  • the dosage is determined in a mouse test, e.g. using DIO B6 mice, at six weeks of age, mice are fed high fat diet to induce obesity, e.g. a 60 kcal % fat diet.
  • the appropriate dosage can be correlated with reduced obesity symptoms, in particular fat mass or body weight.
  • Example dosages are at least 0.01 mg/kg, at least 0.1 mg/kg, at least 1 mg/kg, at least 10 mg/kg and/or up to 1 mg/kg, up to 10 mg/kg, up to 100 mg/kg, up to 1 g/kg, and any dosages in between.
  • Preferred dosage ranges are between 0.01 mg/kg and 1 g/kg, preferably between 0.1 mg/kg and 100 mg/kg.
  • Vandetanib also known as Zactima; ZD6474; 4-Bromo-2-fluorophenyl)-[6-methoxy-7-(1-methyl-piperidin-4-ylmethoxy)-quinazolin-4-yl]-amine is an orally available tyrosine kinase inhibitor (TKI).
  • TKI tyrosine kinase inhibitor
  • Vandetanib is currently in clinical trials for the treatment of various cancers, including colorectal cancer, non-small cell lung cancer, hepatocellular carcinoma and medullary thyroid cancer. Vandetanib is currently under review by the FDA Oncologic Drugs Advisory Committee (ODAC) proposed to be indicated for the treatment of patients with unresectable locally advanced or metastatic medullary thyroid cancer.
  • ODAC Oncologic Drugs Advisory Committee
  • An oral dose of 300 mg once daily is the maximum tolerated dose in humans.
  • Doses used in the clinic range between 100 mg and 300 mg.
  • Dasatinib is also known as BMS-354825. Dasatinib is indicated for the treatment of adults with chronic, accelerated, or myeloid or lymphoid blast phase chronic myeloid leukemia (CML) with resistance or intolerance to prior therapy including imatinib.
  • CML chronic myeloid leukemia
  • a recommended oral starting dose of dasatinib in chronic phase CML is 100 mg once daily.
  • the recommended starting dose for accelerated, myeloid, or lymphoid blast phase CML or Philadelphia chromosome-positive ALL is 70 mg twice daily.
  • Doses of up to 140 mg once daily have been used in patients with chronic phase CML, and up to 100 mg twice daily in those with advanced phase CML, or with ALL. It may also be administered 15 to 240 mg per day (60 kg adult human dose), preferably orally.
  • Sorafenib and the tosylate salt form Sorafenib Tosylate (chemical name 4-(4- ⁇ 3-[4-chloro-3(trifluoromethyl)phenyl]ureido ⁇ phenoxy)-N2-methylpyridine-2-carboxamide-4-methylbenzenesulfonate) inhibits tumour cell proliferation and angiogenesis by targeting RAF Kinases and VEGF Receptors.
  • Sorafenib is generally prepared as its tosylate salt form.
  • Sorafenib and pharmaceutically acceptable salts thereof are disclosed in WO0042012.
  • Sorafenib is also disclosed in WO0041698. Both these patents also disclose processes for the preparation of sorafenib.
  • Sorafenib is approved for the treatment of primary kidney cancer (advanced renal cell carcinoma) and advanced primary liver cancer (hepatocellular carcinoma).
  • the maximum tolerated does in humans is an oral administration of 400 mg twice daily.
  • Sorafenib antagonizes activity of gene CG8222 (PDGF- and VEGF-receptor related). Whole body and fat body-specific knockdown of this gene resulted in a loss of trigylcerides in the fly.
  • the human orthologue of this gene is KDR (kinase insert domain receptor (a type III receptor tyrosine kinase. It functions as mediator of endothelial proliferation, survival, migration, tubular morphogenesis and sprouting.
  • the signalling and trafficking of this receptor are regulated by multiple factors, including Rab GTPase, P2Y purine nucleotide receptor, integrin alphaVbeta3 and T-cell protein tyrosine phosphatase.
  • Sorafenib may be administered orally and has a half life of 25-48 hours.
  • the dosage can be between 50 and 600 mg (adult human dose), preferably about 200 mg.
  • Tanespimycin also known as 17-allylamino-demethoxygeldamycin (17-AAG) and KOS-953, is an ansamycin anti-biotic which acts as an anti-tumour agent. Specifically, Tanespimycin binds and inhibits Hsp90 (Heat shock protein 90). Hsp90 is a protein chaperone that binds to signalling proteins, known as client proteins. These client proteins include key cancer-relevant targets such as mutated p53, Bcr-Abl, Her2, Akt, Raf-1, B-Raf, and others. Tanespimycin is able to disrupt the Hsp90-client protein complexes and lead to the degradation of the client proteins. Tanespimycin and the related compound Alvespimycin (INN) also known as 17-dimethylamino-geldanamycin (17-DMAG) or KOS-1022 are less toxic analogues of geldanamycin (GA).
  • Hsp90 Heat shock protein 90
  • client proteins include key cancer-relevant targets such
  • Tanespimycin has been investigated for the treatment of patients with Relapsed-refractory Multiple Myeloma, Metastatic Papillary or Clear Cell Renal Cell Carcinoma, Recurrent Advanced Ovarian Epithelial or Primary Peritoneal Cavity Cancer, Metastatic Breast Cancer and Refractory or Advanced Solid Tumours or Hematologic Malignancies.
  • Tanespimycin is water insoluble, and thus it is administered to patients intravenously using organic solvents such as DMSO.
  • organic solvents such as DMSO.
  • a formulation of tanespimycin, KOS-953, that contains Cremophory EL (polyethoxylated castor oil) rather than DMSO has also been developed.
  • Recommended phase II doses of 295 mg/m2, 308 mg/m2, and 450 mg/m2 have been administered to patients.
  • HSP90AA1 The human orthologue of this gene is the heat shock protein HSP90AA1.
  • HSP90 proteins are highly conserved molecular chaperones that have key roles in signal transduction, protein folding, protein degradation, and morphologic evolution. HSP90 proteins normally associate with other cochaperones and play important roles in folding newly synthesized proteins or stabilizing and refolding denatured proteins after stress.
  • HSP90AA1 is one of the two major cytosolic HSP90 proteins.
  • 17-N-Allylamino-17-demethoxygeldanamycin may be administered i.p., i.v., or oral, preferably i.p., e.g. at doses of 60, 40, and 26.67 mg/kg i.p. and oral doses of 40 mg/kg.
  • the dose may be between 1 mg/kg of body weight to 500 mg/kg, preferably at least 20 mg/kg or even above 80 mg/kg.
  • S-17092 or “S17092-1”, (2S,3aS,7aS)-1 ⁇ [(R, R)-2-phenylcyclopropyl]carbonyl ⁇ -2-[(thiazolidin-3-yl)carbonyl]octahydro-1H-indole, is a selective inhibitor of the enzyme Prolyl endopeptidase. This enzyme is involved in the metabolic breakdown of a number of neuropeptide neurotransmitters in the brain and so inhibiting the action of the enzyme increases the activity of these neuropeptides. This produces nootropic effects which make S-17092 a promising and novel treatment for neurodegenerative conditions such as Alzheimer's disease and Parkinson's disease. S17092 might possess some mood-stabilizing potential in addition to its cognition-enhancing properties.
  • S-17092 has been administered orally to patients at doses of 100, 400, 800 and 1200 mg once daily (Morain et al., 2000).
  • CG5355 Knockdown of the drosophila gene CG5355 resulted in a loss of triglyceride levels in the fly. Tissue specific deletion in the liver and fat body also lead to a reduction of triglyceride levels in the fly.
  • a human orthologue of CG5355 is PREP.
  • PREP Prolyl endopeptidase
  • cytosolic prolyl endopeptidase that cleaves peptide bonds on the C-terminal side of prolyl residues within peptides that are up to approximately 30 amino acids long. Prolyl endopeptidases have been reported to be involved in the maturation and degradation of peptide hormones and neuropeptides.
  • Lintopride (also referred to as Lintopril) is a 5HT-4 antagonist with moderate SHT-3 antagonist properties. Lintopride has been shown in humans to increase the lower oesophageal sphincter (LOS) motility basal tone without affecting LOS physiological relaxation after swallowing and leads to an increase of peristaltic waves in the oesophagus.
  • LOS oesophageal sphincter
  • HTR4 Human orthologue of this gene is HTR4.
  • This gene is a member of the family of serotonin receptors, which are G protein coupled receptors that stimulate cAMP production in response to serotonin (5-hydroxytryptamine).
  • the gene product is a glycosylated transmembrane protein that functions in both the peripheral and central nervous system to modulate the release of various neurotransmitters.
  • Fenoprofen non-steroidal anti-inflammatory drug
  • Fenoprofen calcium is used for symptomatic relief for rheumatoid arthritis, osteoarthritis, and mild to moderate pain.
  • Fenoprofen is taken orally at doses ranging from 200 mg up to a maximum recommended dose of 3.2 g per day.
  • Sulfaphenazole is a sulfonamide antibacterial and a specific inhibitor of CYP2C9. It blocks the pro-inflammatory and atherogenic effects of linoleic acid (increase in oxidative stress and activation of AP-1) mediated by CYP2C9.
  • Sulfaphenazole has been administered to patients by intravenous and intra-arterial perfusion (0.03 ⁇ g/100 ml tissue/min) (Giannarelli et al., 2009).
  • CG3466 is a member of the cytochrome P450 enzyme family. Sulfaphenazole functions as an inhibitor of cytochrome function.
  • Fluticasone propionate (Ubizol) is a synthetic corticosteroid derived from fluticasone used to treat asthma and allergic rhinitis (hay fever). It is also used to treat eosinophilic esophagitis. Fluticasone propionate is delivered as an aerosol formulation and is also available as a cream for the treatment of eczema and psoriasis.
  • Fluticasone propionate functions as a Smoothened (Smo) agonist that activate Hedgehog signalling (Wang et al., 2010).
  • the maximum recommended dose for fluticasone propionate aqueous nasal spray is 200 micrograms daily. Intranasal administration of 2 mg (10 times the recommended dose) of fluticasone propionate twice daily for 7 days to healthy human volunteers was well tolerated. Single oral doses up to 16 mg have been studied in human volunteers with no acute toxic effects reported. Repeat oral doses up to 80 mg daily for 10 days in volunteers and repeat oral doses up to 10 mg daily for 14 days in patients were well tolerated.
  • Rolipram is a phosphodiesterase IV inhibitor with antidepressant properties. It is an anti-inflammatory drug being studied as a possible alternative to current antidepressants. Recent studies show that rolipram may have antipsychotic effects. Other beneficial effects of rolipram include improved long term memory, increased wakefulness, and increased neuroprotection. Rolipram shows promise in ameliorating Alzheimer's disease, Parkinson's disease and also in the regeneration of severed spinal cord axonal bodies.
  • Rolipram can be administered orally or intravenously usually at doses ranging from 0.001-10 mg per day.
  • Febuxostat is an inhibitor of xanthine oxidase. Xanthine oxidase functions to successively oxidize both hypoxanthine and xanthine to uric acid. Inhibition of xanthine oxidase by febuxostat reduces production of uric acid. Febuxostat is indicated for use in the treatment of hyperuricemia and gout. The recommended dose is of 40 mg or 80 mg orally once daily.
  • Verapamil and its salt Verapamil Hydrochloride is an L-type calcium channel blocker of the Phenylalkylamine class. It has been used in the treatment of hypertension, angina pectoris, cardiac arrhythmia, and migraine. Verapamil has also been used as a vasodilator during cryopreservation of blood vessels. It is a class 4 antiarrhythmic. The maximum recommended human daily dose is 480 mg/day by oral administration.
  • Erlotinib preferably used in its hydrochloride salt form (trade name Tarceva), is a drug used to treat non-small cell lung cancer, pancreatic cancer and several other types of cancer. It is a tyrosine kinase inhibitor, which acts on the epidermal growth factor receptor (EGFR).
  • EGFR epidermal growth factor receptor
  • Gefitinib (trade name Iressa) is an EGFR inhibitor drug used in the treatment of advanced non-small cell lung cancer (NSCLC).
  • Lapatinib preferably used in the form of lapatinib ditosylate (USAN) (Tykerb/Tyverb, GSK), is an orally active drug for treatment of breast cancer and other solid tumours. It is a dual tyrosine kinase inhibitor which disrupts the HER2 growth receptor pathway.
  • Axitinib is a small molecule tyrosine kinase inhibitor. It has been shown to significantly inhibit growth of breast cancer in xenograft models and has been successful in trials with renal cell carcinoma (RCC) and several other tumour types.
  • RRC renal cell carcinoma
  • Pazopanib is a multi-targeted receptor tyrosine kinase inhibitor. It has been approved for treatment of renal cell carcinoma. Pazopanib may also be active in ovarian cancer and soft tissue sarcoma and in the treatment of non-small cell lung carcinoma.
  • Semaxanib also known as Semaxinib or SU 5416
  • Semaxanib is a tyrosine kinase inhibitor that has been withdrawn from clinical trials after failing to show efficacy in the treatment of patients with advanced stage colorectal cancer.
  • Further preferred compounds are associated with the gene CG6919 and its human orthologue HTR4 selected from the list of cisapride, mosapride, piboserod, prucalopride, tegaserod, tropisetron, renzapride, and zacopride:
  • Cisapride is a gastroprokinetic agent, a drug which increases motility in the upper gastrointestinal tract. Cisapride increases muscle tone in the esophageal sphincter in patients with gastroesophageal reflux disease. It has also been used to treat bowel constipation.
  • Mosapride is a gastroprokinetic agent which accelerates gastric emptying and is used for the treatment of acid reflux, irritable bowel syndrome and functional dyspepsia.
  • Piboserod also known as SB 207266
  • SB 207266 is used for the treatment of atrial fibrillation and irritable bowel syndrome. It is also being investigated as a treatment for heart failure
  • Prucalopride treats the impaired motility associated with chronic constipation, thus normalising bowel movements.
  • Renzapride is a gastroprokinetic agent and antiemetic, which was being investigated for the treatment of constipation predominant irritable bowel syndrome (IBS-C). It is also potentially effective for irritable bowel syndrome with alternating stool pattern (IBS-A). However it failed to show efficacy over placebo in Phase III clinical trials and development was discontinued.
  • IBS-C constipation predominant irritable bowel syndrome
  • IBS-A alternating stool pattern
  • Tegaserod functions as a motility stimulant that stimulates gastrointestinal motility and the peristaltic reflex. It was approved for the treatment of irritable bowel syndrome and constipation.
  • Tropisetron is an antiemetic used to treat nausea and vomiting following chemotherapy. It has also been used experimentally as an analgesic in the local treatment of tendinopathies and myofascial pain syndromes.
  • Zacopride been shown to have many activities including anxiolytic and nootropic effects. It has also been shown to have antiemetic and pro-respiratory effects, both reducing sleep apnea and reversing opioid-induced respiratory depression in animal studies.
  • inventive obesity tests revealed pharmaceutical compounds that are well known to be therapeutically applicable for the treatment of human conditions and diseases.
  • the compounds may now also be used for the treatment of obesity and associated secondary diseases such as diabetes or the metabolic syndrome.
  • the full list of compounds according to table 1 provides new therapeutic concepts.
  • Further compounds to be used in any form of treatment are selected from any one of (5-(2-methoxy-5-chloro-5-phenyl)furan-2-ylcarbonyl)guanidine, (E)-4-(2-(2-(N-acetyl-N-(4-methoxybenzenesulfonyl)amino)stilbazole)) 1-oxide, (melle-4)cyclosporin, 1-(1-cyclohexylethylamino)-4-phenylphthalazine, 1-(2-methoxyphenyl)-4-(4-(2-phthalimido)butyl)piperazine, 15-deoxyprostaglandin J2,17-(allylamino)-17-demethoxygeldanamycin, 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin, 1-aminooxy-3-aminopropane
  • the compound modulates at least two, three, four, five or six or more of these genes (or orthologues).
  • Further compounds suitable to modulate gene function include the administration of therapeutic proteins or nucleic acids, such as transgenes or inhibitory nucleic acids (RNAi molecules, siRNA, antisense RNA or DNA). Such interfering nucleic acids bind messages of the genes leading to degradation and reduced gene expression.
  • therapeutic proteins include the gene products of these genes (as agonists) or antibodies which specifically bind these proteins (as antagonists, but also as agonists if protein activity is increases—such as by binding and blocking an inhibitor binding site).
  • the inventive compounds can act as either agonist by increasing the gene function (via mRNA regulation or interaction with the protein) of a protein in the enzymatic pathway of any one of the above listed genes or an antagonist in said pathways.
  • the antagonizing or activating (agonist) activity of the compounds acts preferably on the identified obesity genes (including their gene product) themselves or on a binding partner thereof. In preferred embodiments antagonists of the obesity genes are used.
  • odorant receptor genes 10a, 56a, 65a, 67a, 83cd, CG10407 and gustatory receptors 98b and 36b can be targeted, in particular, suppressed or antagonized.
  • the dopamine receptor DopR2, two octopamine receptors (TyrR and oa2) and the Nmda-receptor associated protein Nmda1 In addition, altered fat deposition was observed in response modification of genes involved in glucose/lipid mobilization including fructose-1,6-bisphosphatase (fbp), the two members of the glycerol phosphate shuttle (CG31169 and Gpo-1), mitochondrial acyl-carrier protein 1 (mtacp1), ADP/ATP translocase 2 (Ant2), pyruvate carboxykinae (CG1516), and fatty-acid synthetase (fasn).
  • fructose-1,6-bisphosphatase fbp
  • CG31169 and Gpo-1 mitochondrial acyl-carrier protein 1
  • ADP/ATP translocase 2 ADP/ATP translocase 2
  • pyruvate carboxykinae CG1516
  • genes to be modified according to the present invention includes the Drosophila orthologues of glucagon (akh), the insulin receptor (dInR), as well as the downstream kinases PI3-kinase (dPI3K), ribosomal-S6-kinase (dRSK), the CREB-coactivator dTORC, and the critical TOR-signaling constituent dTSC-1, Drosophila homologues of the critical early adipogenic regulators NCOR1/2, Jag1/2, and TAK1, or the metabolic regulators CRTC1/2 and pyruvate carboxylase (PC).
  • the present invention has identified human orthologs (table 1) that can be targeted by the inventive use of the therapeutic compounds.
  • genes listed in table 1 those shown in example 1.2, in particular those illustrated in examples 1.3, 1.4 or 1.5, can be modified by therapeutic administration of suitable compounds.
  • Preferred genes to be modified according to the present invention are those discussed above, as well as the LSD (Lipid Storage Droplet) and LPD (LiPid Depleted) genes, the Drosophila insulin like peptides (lip's), the glucagon homologue akh and its receptor akhr, as well as adipose (adp), bubblegum (bbg), and the Drosophila SREBP homologue, HLH106, CG8451, of course, as well as their human orthologues.
  • LSD Lipid Storage Droplet
  • LPD LiPid Depleted
  • Definition 1 The method of reducing weight and/or body fat in a subject comprising the administration of a therapeutic compound selected from the compounds of table 1.
  • Definition 2 The method of reducing weight and/or body fat in a subject or to treat obesity comprising the administration of an antagonist of one or more of the genes selected from CG30184, CG10369, CG32401, CG2374, CG8693, CG14909, CG13299, CG7847, CG30462, CG30462, CG15169, CG1650, CG6577, CG30491, CG4373, CG10407, CG2198, CG6356, CG5744, CG9506, CG31169, CG1728, CG9220, CG15625, CG5550, CG13088, CG13188, CG14968, CG1503, CG1666, CG14869, CG2702, CG2984, CG4394, CG9922, CG14529, CG17781, CG17781, CG9153, CG15178, CG5641, CG3879, CG15579, CG1422,
  • Definition 3 The method according to definition 1 or 2, characterized in that the compound or antagonist is administered in a effective therapeutic dose.
  • Definition 4 The method of any one of definitions 1 to 3, characterized in that the compound is administered topical, enteral or parenteral, in particular preferred oral or rectal, intravenous, intraarterial, intramuscular, subcutaneous, intradermal or intraperitoneal, transdermal, transmucosal or inhalational.
  • Definition 5 The method of any one of definitions 1 to 4, characterized in that the subject is mammal, preferably a human.
  • Definition 6 The method of any one of definitions 1 to 5, characterized in that the compound or antagonist is provided in a medicament.
  • Definition 7 The method of any one of definitions 1 to 6, characterized in that the compound or antagonist is provided together with a pharmaceutically acceptable carrier or buffer.
  • Definition 8 The method of any one of definitions 1 to 6, characterized in that the compound or antagonist is administered in a dosage of between 0.01 mg/kg and 1 g/kg.
  • Definition 9 Use of a compound as defined in definitions 1 or an antagonist as defined in definition 2, preferably further defined as in any one of definitions 3 to 8, for the manufacture of a medicament for the therapeutic administration to reduce body weight and/or body fat or to treat or prevent obesity in a subject.
  • FIG. 1 Genome-wide RNAi screen for obesity factors in adult Drosophila in vivo.
  • FIG. 2 Basal triglyceride and protein contents in Drosophila . Related to FIG. 1 .
  • A Triglyceride content of w1118 Drosophila strain measured throughout development using a medium-throughput 96-well plate based system with a colorimetric determination endpoint.
  • C Individual triglyceride and protein content in 80 different sets of 8 male flies each measured 2 to 4 days after enclosure. Measurement was made to validate the medium throughput experimental system designed for the genome-wide screen.
  • D Pie chart summarizing the most depleted functional classifications using gene ontology for biological processes for all annotated genes with Z-scores in excess of +/ ⁇ 1.65 through three rounds of testing.
  • FIG. 3 Tissue-specific regulation of fat storage.
  • B-E Left panels show the mean changes in triglycerides after tissue-specific knockdown for the top-scoring fat-enhancing (red lines) and fat-depleting (blue lines) genes in each tissue category.
  • FIG. 4 Interaction network for candidate obesity genes. Related to FIG. 1 .
  • the interaction network was assembled using Cytoscape 2.6.2 based on interactions retrieved from STRING, DROIDB, and BIOGRID.
  • Datasets consisted of yeast-2-hybrid, text-mining, and database annotations (e.g. KEGG). Assembly of the visual layout was performed using manual modification of an automated forcedirected layout. Insets highlight the location of both the hedgehog and insulin signaling pathways.
  • FIG. 5 Analysis of tissue-specificity reveals hedgehog signaling as a fat-body specific regulator of triglyceride levels.
  • Triglyceride responses of candidate genes Changes in adiposity in RNAi lines with the most tissue-restricted responses in the (A) pan-neuronal, (B) muscle, (C) oenocyte, and (D) fat-body compartments.
  • E Heat-map of adiposity observed in UAS-RNAi transgenic fly lines targeting available annotated hedgehog and notch pathways. Changes are relative to averages of control RNAi-lines and w1118 flies crossed to the respective GAL4 drivers. Genes are grouped according to their role as either positive (+) or negative ( ⁇ ) effectors, or as mediators of ligand processing and release (Lp).
  • FIG. 6 Tissue-specificity of hedgehog and OxPhos pathway triglyceride changes. Related to FIG. 5 .
  • B Triglyceride changes in ppl-GAL4 driven UAS-RNAi transgenic lines targeting hedgehog specific ligand processing and release genes.
  • (D) Triglyceride responses of the same oxidative phosphorylation targeting RNAi-transgenic lines to heat-shock induced ubiquitous knockdown. Data are presented as mean ⁇ s.e.m. n 4.
  • FIG. 7 aP2-Sufu mice display white adipose tissue specific lipoatrophy.
  • A aP2-SufuKO mice are born healthy and at Mendelian ratios.
  • B NMR imaging of an aP2-SufuKO mouse and a Sufu-expressing littermate control.
  • C Cross-section at the level of the scapulae show unaltered brown adipose depots (yellow dashed lines).
  • D PCR revealed robust deletion of the Sufu allele (Sufu 4-8) in both BAT and WAT depots. Minor deletion was detected in skeletal muscle, lung, and the spleen.
  • E Tissue dissection white adipose tissue (WAT; upper panel) and brown adipose tissue (BAT; lower panel) revealed fully developed brown adipose depots despite severely compromised white adipose tissue depots in aP2-SufuKO mice. Dashed lines mark white adipose tissue.
  • F,G Representative H&E stained sections of (F) brown (BAT) and (G) white (WAT) adipose tissues from aP2-SufuKO and control littermate mice.
  • FIG. 8 IBMX and dexamethasone dependence of hedgehog signaling in adipocytes and generation of lipoatrophic Sufu mutant mice related to FIG. 7 .
  • the conditional allele encorporates two Cresensitive loxP sites flanking exons 4-8 of the Sufu open reading frame. Numbered boxes indicate exons.
  • E H&E stained sections of skin highlight a clear reduction in cutaneous adipose tissue.
  • FIG. 9 Loss of weight in Vandetanib administered mice.
  • C57BL6/J DIO mice were administered 40/mg/kg/day by oral gavage. The mice were weighed daily and the values were expressed as a percentage of the starting weight (day 1). By day 13 of administration there was significant loss of weight in the vandetanib administered group compared to the vehicle control (p ⁇ 0.05; unpaired student t test) which was maintained for the duration of the experiment. Error bars represent standard error of the mean.
  • FIG. 10 Lower fasting glucose levels in vandetanib administered mice.
  • the mice were subjected to an Insulin Tolerance Test. Briefly the mice were fasted for 2 hours. Blood was collected at time 0 prior to injection of insulin. Blood was collected at 15, 30, 45 and 60 minutes after injection to measure the glucose response. Although the insulin response was similar in both groups, the vandetanib administered mice exhibited lower fasting blood glucose levels compared to the controls (p ⁇ 0.05; unpaired student t test). Error bars represent standard error of the mean.
  • FIG. 11 Oral glucose tolerance test (oGTT) in vandetanib administered mice compared to vehicle controls. Mice were fasted overnight and on day 35 a blood sample was taken to measure the fasting glucose levels (time 0). The mice were administered glucose, blood was collected and the glucose levels were measured 15, 45 and 60 minutes after glucose administration. Vandetanib administered mice show an improved glucose response compared to the vehicle administered group 15, 45 and 60 minutes after glucose administration (p ⁇ 0.05; unpaired student t test). Error bars represent standard error of the mean.
  • FIG. 12 Measurement of perigonadal fat pad weights.
  • the vandetanib and vehicle administered mice were sacrificed on day 38 of administration.
  • the perigonadal fat pads were dissected and the weight (grams) was expressed as a ratio compared to body length (cm).
  • Each point on the graph represents the average weight (g) of the two perigonadal fat pads from each mouse expressed as a ratio to body length (cm).
  • the vandetanib administered mice have a proportionally lower fat pad mass compared to vehicle controls (p ⁇ 0.05; unpaired student t test). Error bars represent standard error of the mean.
  • FIG. 13 Loss of weight in dasatininb administered mice.
  • C57BL6/J DIO mice were administered 5/mg/kg/day for 27 days. The mice were weighed daily and the values were expressed as a percentage of the starting weight (day 1). On day 28 there was significant loss of weight in the dasatinib administered group compared to the vehicle control (p ⁇ 0.001; unpaired student t test). Error bars represent standard error of the mean.
  • FIG. 14 Improved insulin response in dasatinib administered mice on day 15 of administration.
  • An oral glucose tolerance test (oGTT) was performed in mice which were fasted overnight.
  • a blood sample was taken to measure the fasting glucose levels (time 0).
  • the mice were administered glucose, blood was collected and the glucose levels measured 15, 30, 45 and 60 minutes after glucose administration.
  • Dasatinib administered mice show an improved early response to glucose administration at the 15 minute (p ⁇ 0.01), 30 and 45 minute (p ⁇ 0.05) time point compared to the vehicle administered group. Error bars represent standard error of the mean.
  • FIG. 15 Improved insulin response in dasatinib administered mice on day 29.
  • Dasatinib administered mice show improved glucose clearance 45 (p ⁇ 0.05) and 60 minutes (p ⁇ 0.01) after glucose administration compared to the vehicle administered group (Student t-test; p ⁇ 0.05). Error bars represent standard error of the mean.
  • RNAi transgenic-RNAi screen for fat content in adult Drosophila using a heat shock-inducible Hsp70-GAL4 system ( FIG. 1A ).
  • Triglycerides the major lipid storage form in animals, were chosen as a direct measure of fly adiposity.
  • Total fly triglyceride levels were measured by colorimetric determination and normalized to protein ( FIG. 1A ).
  • FIG. 1B we were able to track triglyceride changes throughout development as well as to clearly distinguish sex-specific differences in fat content
  • FIG. 1C FIG. 1C .
  • RNAi lines targeting genes previously reported to regulate fat content revealed lipid alterations consistent with expected lean ( FIG. 1D ) and obese ( FIG. 1E ) phenotypes. Included were the LSD (Lipid Storage Droplet) and LPD (LiPid Depleted) genes as well as the Drosophila insulin like peptides (Ilp's), the glucagon homologue akh and its receptor akhr, as well as adipose (adp), bubblegum (bbg), and the Drosophila SREBP homologue, HLH106 (Gronke et al., 2007; Hader et al., 2003; Min and Benzer, 1999).
  • LSD Lipid Storage Droplet
  • LPD LiPid Depleted
  • Gene ontology (GO) based pathway analysis for biological process revealed enrichment of gene sets involved in cell fate determination, cellular protein metabolic processes, signal transduction, intracellular transport, and regulation of smoothened signaling.
  • Pathways most depleted during the screen i.e. those not relevant to fat regulation, included genes regulating behavior, cell cycle, organelle organization and biogenesis, locomotory behavior, and chromosome organization.
  • a network interaction assembly based on yeast-2-hybrid, text-mining, and pathway database information on the Drosophila hits and their mammalian orthologues revealed an interaction network map ( FIG. 4 ) highlighting genes of development, nutrient transport, cell cycle regulation, the proteasome, protein translation, and chromatin remodeling.
  • the candidate gene list included a number of potential regulators of feeding control. For instance, six odorant and two gustatory receptor genes were targeted (Odorant receptors 10a, 56a, 65a, 67a, 83cd, and CG10407; gustatory receptors 98b and 36b). Also, the dopamine receptor DopR2, two octopamine receptors (TyrR and oa2) and the Nmda-receptor associated protein Nmda1 all showed reduced body fat content following RNAi induction.
  • RNAi knockdown of known mediators of glucose/lipid mobilization including fructose-1,6-bisphosphatase (fbp), the two members of the glycerol phosphate shuttle (CG31169 and gpo-1), mitochondrial acyl-carrier protein (mtacp1), ADP/ATP translocase 2 (Ant2), pyruvate carboxykinae (CG1516), and fatty-acid synthetase (fasn).
  • fructose-1,6-bisphosphatase fbp
  • mtacp1 mitochondrial acyl-carrier protein
  • ADP/ATP translocase 2 ADP/ATP translocase 2
  • pyruvate carboxykinae CG1516
  • fatty-acid synthetase fatty-acid synthetase
  • dPI3K downstream kinases PI3-kinase
  • dRSK ribosomal-S6-kinase
  • dTORC CREB-coactivator dTORC
  • critical TOR-signaling constituent dTSC-1 Drosophila orthologues of glucagon (akh), the insulin receptor (dInR), as well as the downstream kinases PI3-kinase (dPI3K), ribosomal-S6-kinase (dRSK), the CREB-coactivator dTORC, and the critical TOR-signaling constituent dTSC-1
  • Drosophila homologues of the critical early adipogenic regulators NCOR1/2, Jag1/2, and TAK1 Ross et al., 2004; Suzawa et al., 2003; Yu et al., 2005
  • the metabolic regulators CRTC1/2 and pyruvate carboxylase (PC) Altarejos et al., 2008; Koo et al., 2005; Zhang et al., 1995.
  • RNAi-lines of the 462 primary screen candidate genes were crossed to four independent GAL4 drivers with pan-neuronal (nsyb-GAL4), muscle (C57-GAL4), oenocyte (oe-GAL4), and fat-body (ppl-GAL4) specificity, and their respective triglyceride levels determined ( FIG. 3A ).
  • RNAi lines most strongly regulating fat-content after pan-neuronal (nsyb-GAL4) knockdown elicited little or no change in fly triglyceride levels when induced in the muscle, oenocyte or fat body FIG. 3B .
  • Muscle-specific gene silencing (C57-GAL4) by contrast, enriched for genes that also elicited significant changes in triglycerides when targeted in oenocytes and the fat-body ( FIG. 3C ).
  • RNAi-lines responding most substantially to oenocyte and fat-body specific knockdown displayed a coordinate and reciprocal pattern of adiposity regulation ( FIGS.
  • the neuronal hits are: CG5436, CG2091, CG17461, CG11339, CG11202, CG5245, CG14911, CG30075, CG16836, CG5147, CG17184, CG10728, CG17742, CG4851, CG5381, CG18563, CG18268, CG10542, CG12015, CG4152, CG32669, CG32149, CG11756, CG12691, CG12595, CG32210, CG1279, CG17255, CG2260, CG14024, CG2146, CG7776, CG31132, CG3497, CG9936, CG10152, CG14842, CG6043, CG8515, CG9946, CG17819, CG11125, CG2145, CG12030, CG1759, CG1921, CG
  • the leptin/AgRP/POMC axis exemplifies the profound neuronal dependency of feeding behaviour, metabolic rate, insulin resistance and thus, of obesity risk. Flies do not possess known homologues to this axis but their feeding behavior is also neuronally anchored. Approximately one third of the primary screen hit list elicited triglyceride changes >25% when crossed with the neuronal nsyb-GAL4 driver. A select number exhibited tight neuronal restriction in their response ( FIG. 5A ). Included was the Drosophila homologue for SLC5A8 (CG8451; FIG. 5A ) a neuronal fatty-acid and lactate transporter.
  • fatty acids are sensed by neuronal processing of lactate generated by adjacent glial cells.
  • lines targeting homologues of glucagon (akh, neuronally secreted in Drosophila ), and the neuronal Zn-transporter SLC39A10 both displayed tight neuronal responses.
  • TSC1 (dTSC1), a critical regulator of the amino acid responsive TOR-signaling pathway, showed marked neuronal and fat-body specific responsiveness ( FIG. 5D ). It is likely that aside from peripheral regulation of nutrient storage, TOR signaling in the CNS might relay amino acid status to feeding behaviour.
  • Additional neuronal responsive targets likely to play a direct role in nutrient sensing included the odorant/gustatory receptors Obp56a and TyR.
  • Obp56a and TyR odorant/gustatory receptors
  • FIG. 5B Several genes showed tight muscle-specificity ( FIG. 5B ), including homologues of the proline biosynthetic PYCR1 (P5cr), the glycogen debranching enzyme AGL (CG9485), and the fbp (fructose-1,6-bisphosphatase), a key regulator of glycolysis.
  • Mevalonate decarboxylase CG8239
  • ARV1 sterol regulating enzyme
  • IM10 TLR-signaling
  • CG3213 ribosome and protein translation
  • Furl proteolysis
  • CG5591 transcriptional regulation
  • microRNA mediated silencing 5 mg5
  • Oenocyte- and fat body-specific knockdown analyses also identified genes involved in glycerol and lipid metabolism (FIG. 5 C,D). For instance, genes related to insulin signaling including the homologues of PP1 (inhibitory subunit 15b), S6KII, EIF2B, PI3K, and the insulin receptor itself (IR). Also, direct mediators of lipid and glucose metabolism were identified, such as homologues of the ADP/ATP symporter ANT, NDUFAB1, GDPD, and GPD2. The latter, part of the glycerol-phosphate shuttle, regulates glycolytic rate and ROS production.
  • mice lacking GPD2 exhibit a 40% reduction in white adipose mass (Brown et al., 2002) and share a number of phenotypic features with deficiencies of glycerol kinase (GK), another enzyme found using the oenocyte-specific driver.
  • GK glycerol kinase
  • T3dh an iron-dependent regulator of fatty acid and ketone body metabolism
  • Cyp6a2 cytochrome P450 proteins catalyze numerous steps of cholesterol, steroids and lipids synthesis
  • the Drosophila homologue of the fatty acid elongase ELOVL6 the Drosophila homologue of the fatty acid elongase ELOVL6.
  • Elov16 ⁇ / ⁇ mice develop marked obesity and hepatosteatosis and show protection from hyperinsulinemia, hyperglycemia, and hyperleptinemia (Matsuzaka et al., 2007).
  • Using fat-body specific knockdown we also hit the Drosophila homologue of ELOVL7.
  • FOG. 5 C,D we found multiple previously uncharacterized genes that regulate fat content in an oenocyte- and/or fat body-dependent manner.
  • our screen has revealed a large number of general and tissue specific candidate fly genes and multiple pathways that control triglyceride storage levels.
  • aP2-SufuKO Fat-specific Sufu knockout animals
  • FIG. 8C Fat-specific Sufu knockout animals
  • Sufu is a potent endogenous inhibitor of hedgehog signaling in mammals.
  • Sufu flox/flox mice were crossed to the adipose-tissue deleting aP2-Cre transgenic line ( FIG. 8C ) and the resulting aP2-SufuKO animals were born healthy and at Mendelian ratios.
  • PCR amplification revealed target deletion in both white (WAT) and brown (BAT) adipose tissue (FIG. 7 A,D).
  • aP2-SufuKO mice displayed an immediate and obvious lean phenotype.
  • MRI analysis revealed a significant and global reduction in white adipose tissue mass, including subcutaneous, perigonadal, and mesenteric depots ( FIG. 7B ).
  • cross-sectional examination of the interscapular region revealed fully developed BAT depots of both normal size and lipid content (FIG. 7 B,C).
  • WAT and BAT depot weights corroborated the divergent WAT/BAT phenotype, with an ⁇ 85% reduction in perigonadal fat pad mass in aP2-SufuKO mice concomitant with unaltered BAT mass ( FIG.
  • FIG. 8D Tissue weight and histological analyses confirmed lack of any remarkable phenotype in multiple other tissues including pancreas and liver (no indication of steatosis), and muscle mass was unaffected ( FIG. 8D ). Cutaneous adipose was also markedly diminished ( FIG. 8E ). Whereas the morphology of Sufu-deficient BAT depots was largely indistinguishable from that of control animals (FIG. 7 E,F), examination of multiple WAT pads revealed marked and significant reductions in both adipocyte size (FIG. 7 E,G; FIG. 8F ) and total numbers ( FIG. 8G ) in mutant animals.
  • qPCR showed elevated Gli1, Gli2, and Ptch2 expression in both WAT ( FIG. 7H ) and BAT ( FIG. 7I ), verifying the intended pathway activation in both tissues.
  • deletion of Sufu in fat tissue results in a markedly decreased white fat cell number and, remarkably, in normal brown adipose tissue.
  • mice were divided into cages of 2-4 mice per cage and allowed to acclimatise to the new housing conditions for at least 2 weeks. The mice were weighed every week to monitor their weight and ensure that the mice are either gaining weight or stabilized prior to initiation of the experiment. Mice were randomly assigned to weight-matched groups for compound administration. Compound dosage and routes of administration were determined based on published literature and pharmacokinetic studies.
  • mice 18 weeks of age, were divided into groups of 2-4 mice of equivalent body weight upon receipt from Jax labs.
  • the Jax labs protocol for feeding and care of diet-induced obese (DIO) C57BL/6J mice is as follows: Male mice are selected at random at four weeks of age and fed a 6% fat (wt/wt) chow diet (Lab Diet® 5k52). At six weeks of age, mice are placed in wean cages in groups of 10 and are fed high fat diet to induce obesity (Research Diets, Inc. D124921, 60 kcal % fat). Mice have ad libitum access to food and water. Upon receipt of the animals from Jax labs, animals were kept under similar housing and feeding conditions to those at Jax labs ie. mice continued to receive a high fat diet (Test Diet® 58Y1 60% energy from Fat).
  • Modulator compounds of the new identified genes responsible for triglyceride or fat regulation underwent two rounds of testing. The first round screened all candidate compounds in Drosophila , and positive candidates were subsequently tested in mice induced to be obese through administration of a high fat diet. Two day old W1118 male Drosophila melanogaster were sorted 20 flies per vial and placed for one week on normal fly food in the presence or absence of each test compound. Test compounds were added to the surface of the fly food in liquid form and allowed to absorb into the top-most layer at 3 doses 0.001 umol/kg/day, 1 umol/kg/day, and 1000 umol/kg/day.
  • flies were shock-heated to dryness, and dry weight used as an indicator of adiposity. All flies with dry weights ⁇ 75% of the mean value of control vials were considered positive candidates with obesity lowering activity. Those positive candidates which induced obvious behavioural impairment were removed from the group of positive candidates. Behavioural tests included tapping of the vial (flies should jump into flight) and exposure to light (flies should move towards a light source). All remaining positive candidates were taken forward for analysis in mice.
  • mice 12 weeks of age, were divided into groups of 8-10 mice of equivalent body weight upon receipt from Jax labs.
  • the Jax labs protocol for feeding and care of diet-induced obese (DIO) C57BL/6J mice is as follows: Male mice are selected at random at four weeks of age and fed a 6% fat (wt/wt) chow diet (Lab Diet® 5k52). At six weeks of age, mice are placed in wean cages in groups of 10 and are fed high fat diet to induce obesity (Research Diets, Inc. D124921, 60 kcal % fat). Mice have ad libitum access to food and water.
  • mice Upon receipt of the animals from Jax labs, animals were kept under identical housing and feeding conditions to those at Jax labs ie. mice continued to receive the high fat diet listed above. For all substances known to be orally available in mammals, mice were treated in drinking water at 5 ⁇ and 250 ⁇ the recommended human therapeutic dose. For other compounds dosing was based on published pharmacokinetics in mice or, where unavailable, based on the lowest functional dose in flies (ie. the 1 ⁇ and 50 ⁇ the low-est functional dose in flies). Compounds known to be orally unavailable in mammals were administered once daily by manual injection i.p. in a cellulose injection vehicle at doses determined as above.
  • Body weight as well as food and water intake were monitored over the two week treatment period, and where mean body weight reductions relative to control animals were significant by t-test (p ⁇ 0.05) and exceeded 2 g ( ⁇ 5% of body weight) body fat composition was assessed by weighing total body weight, as well as peri-gonadal and subcutaneous fat pad weight at sacrifice. Compounds where changes in body weight correlate directly with changes in body fat composition were considered positive therapeutic candidates for treating mammalian obesity.
  • Vandetanib also known as ZD6474 is a tyrosine kinase inhibitor that functions as an antagonist of the vascular endothelial growth factor receptor (VEGFR) and the epidermal growth factor receptor (EGFR).
  • VEGFR vascular endothelial growth factor receptor
  • EGFR epidermal growth factor receptor
  • Vandetanib powder was obtained from Selleck Chemicals (S1046). Male C57B16/J DIO mice of 30 weeks of age were weight matched and housed in groups of 2 mice per cage and kept on 12-h light-dark cycle. Food and water were given ad libitum. 8 compound administered mice (experimental) and 7 vehicle administered mice (control) were included in the experiment.
  • Vandetanib was administered in a vehicle consisting of 1% tween in PBS. Control mice were administered vehicle alone, daily, by oral gavage.
  • Vandetanib chosen for this study was 40 mg/kg/d. This has been determined to be an effective dose for the inhibition of the target VEGFR in various mouse cancer models.
  • Vandetanib was administered at a dose of 50 mg/kg/d by oral gavage in a vehicle of 1% tween 80 with PBS for 4 weeks in an orthopic nude mouse model of human Adenoid Cycstic Carcinoma.
  • vandetanib was well tolerated by the mice and no adverse side effects or loss in body weight was observed (Choi et al 2008). This dose was effective to significantly reduce tumour volume compared to vehicle administered controls (Choi et al 2008).
  • Vandetanib has been administered to mice up to a dose of 100 mg/kg in mice for 35 days with no obvious effect on clinical condition (Wedge et al., 2002).
  • the DIO mice were weighed on the same day prior to the first compound administration (day 1).
  • the mice were weighed on a daily basis during the experiment and monitored for overt signs of toxicity or stress. Vandetanib was well tolerated during the course of the study and no adverse side effects were observed.
  • mice On day 38 of compound administration the mice were sacrificed. The perigonadal fat pads were isolated and weighed. These values were expressed as a proportion of the body length of the mouse ( FIG. 12 ). We observed a reduction of fat pad weight in the vandetanib administered group indicating the loss of weight in these mice is due to loss of fat pad mass (p ⁇ 0.05; unpaired student t test).
  • Vandetanib leads to an almost 10% reduction of body weight that stabilized over the course of the experiment.
  • the reduction in blood glucose levels and improvement of glucose handling are consistent with the observed reduction in adiposity.
  • Dasatinib is a multiple BCR/abl Src family tyrosine kinase inhibitor. It is approved for use in the treatment of chronic myelogenous leukaemia.
  • Dasatinib was obtained as a powder from Selleck chemicals. C57B16/J DIO mice of 19 weeks of age and weighing more than 33 g were weight matched and housed in groups of 4 mice per cage and kept on 12-h light-dark cycle. Food and water were given ad libitum. 5 dasatinib administered mice (experimental) and 4 vehicle administered mice (controls) were used in the experiment. Mice were administered a dose of 5 mg/kg/day daily of Dasatinib intraperitoneally in a vehicle of 1:1 propylene glycol/water. Control animals were administered the vehicle alone.
  • the DIO mice were weighed on the same day prior to the first compound administration (day 1). The mice were weighed on a daily basis during the experiment and monitored for overt signs of toxicity or stress. Dasatinib was well tolerated during the course of the study and no adverse side effects were observed. We observed a significant weight loss in the dasatinib administered mice compared to the vehicle administered controls (FIG. 13). On day 5 we observed a significant weight reduction in the dasatinib group and by day 28 these mice had lost an average of 20% of their starting weight. This represented a statistically significant loss compared to vehicle administered mice (p ⁇ 0.001; unpaired student t test).

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
HK1209035A1 (en) * 2012-05-25 2016-03-24 Berg Llc Methods of treating a metabolic syndrome by modulating heat shock protein (hsp) 90-beta
EP3669881B1 (en) 2014-01-28 2022-03-30 Buck Institute for Research on Aging Compositions for use in the treatment of senescence-assiocated eye disease and disorders
US20170216286A1 (en) 2014-01-28 2017-08-03 Mayo Foundation For Medical Education And Research Killing senescent cells and treating senescence-associated conditions using a src inhibitor and a flavonoid
US20190269675A1 (en) 2014-01-28 2019-09-05 Buck Institute for Research and Aging Treatment of parkinson's disease and other conditions caused or mediated by senescent astrocytes using small molecule senolytic agents
AU2015269054A1 (en) 2014-06-06 2017-01-12 Berg Llc Methods of treating a metabolic syndrome by modulating heat shock protein (HSP) 90-beta
IL234962A0 (en) * 2014-10-02 2015-01-29 Yeda Res & Dev Use of substances to treat fat-related diseases
CN105287552B (zh) * 2015-10-27 2018-03-20 中国科学院广州生物医药与健康研究院 阿西替尼的应用
JP7249397B2 (ja) * 2017-12-27 2023-03-30 日本化薬株式会社 ダサチニブを有効成分とする医薬組成物
CN109464443B (zh) * 2018-10-10 2021-08-17 中国科学院广州生物医药与健康研究院 Linifanib的新应用
WO2020188496A1 (en) * 2019-03-18 2020-09-24 Moshe Rogosnitzky Stable liquid naltrexone compositions
WO2021101814A1 (en) * 2019-11-19 2021-05-27 The George Washington University Intranasal leptin prevents opioid-induced respiratory depression in obesity
JP2023159469A (ja) * 2020-08-24 2023-11-01 国立大学法人 東京大学 肥満症を予防又は治療するための医薬組成物
CN115624980B (zh) * 2022-12-26 2023-03-10 四川大学 一种金属硒基生物催化材料及其制备方法和用途
WO2025081219A1 (en) * 2023-10-19 2025-04-24 St Vincent's Institute Of Medical Research Methods of treating conditions with sik3 inhibitors

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4832958A (en) * 1985-09-30 1989-05-23 Pharlyse Societe Anonyme Galenic forms of prolonged release verapamil and medicaments containing them
US20050090554A1 (en) * 2003-09-12 2005-04-28 John Devane Treatment of gastroparesis and nonulcer dyspepsia with GABAB agonists

Family Cites Families (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2625678B1 (fr) * 1988-01-13 1991-06-07 Delalande Sa Agents anorexigenes a base de n-(quinuclidin-3-yl)-benzamides ou thiobenzamides
FR2681864B1 (fr) * 1991-09-27 1995-03-31 Adir Nouveaux derives bicycliques azotes, leur procede de preparation et les compositions pharmaceutiques qui les contiennent.
JP2002534468A (ja) 1999-01-13 2002-10-15 バイエル コーポレイション ｐ３８キナーゼ阻害剤としてのω−カルボキシアリール置換ジフェニル尿素
WO2000042012A1 (en) 1999-01-13 2000-07-20 Bayer Corporation φ-CARBOXYARYL SUBSTITUTED DIPHENYL UREAS AS RAF KINASE INHIBITORS
IL139321A0 (en) 1999-03-03 2001-11-25 Biogen Inc Methods and compositions for modulating lipid metabolism
WO2002090504A2 (en) * 2001-05-03 2002-11-14 Curagen Corporation Novel antibodies that bind to antigenic polypeptides, nucleic acids encoding the antigens, and methods of use
EP1492525A2 (en) * 2001-08-16 2005-01-05 Probiodrug AG Use of inhibitors of proline endopeptidase to modulate inositol (1,4,5) triphosphate concentration dependent on intracellular signal cascades
KR20030083348A (ko) * 2002-04-22 2003-10-30 주식회사 엠디바이오알파 지방세포 분화 저해 활성을 가지는 프로토베르베린알칼로이드 화합물인 베르베린을 유효성분으로 함유하는비만예방 및 치료
CN1481796A (zh) * 2003-06-13 2004-03-17 吴开敏 治疗肥胖症的药物
WO2005115446A2 (en) * 2004-05-21 2005-12-08 Yale University Detection and use of prolylcarboxypeptidase
US8703769B2 (en) * 2005-07-15 2014-04-22 The University Of North Carolina At Chapel Hill Use of EGFR inhibitors to prevent or treat obesity

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4832958A (en) * 1985-09-30 1989-05-23 Pharlyse Societe Anonyme Galenic forms of prolonged release verapamil and medicaments containing them
US20050090554A1 (en) * 2003-09-12 2005-04-28 John Devane Treatment of gastroparesis and nonulcer dyspepsia with GABAB agonists

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Cortes et al. "Results of Dasatinib Therapy in Patients with Early Chronic-Phase Chronic Myeloid Leukemia". J Clin Oncol, 2009; 28:398-404. *

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20120208836A1 (en) * 2011-02-14 2012-08-16 The Regents Of The University Of Michigan Compositions and methods for the treatment of obesity and related disorders
US10245255B2 (en) * 2011-02-14 2019-04-02 The Regents Of The University Of Michigan Compositions and methods for the treatment of obesity and related disorders
US10590142B2 (en) 2013-05-02 2020-03-17 The Regents Of The University Of Michigan Deuterated amlexanox
US9944652B2 (en) 2013-05-02 2018-04-17 The Regents Of The University Of Michigan Deuterated amlexanox
US11311512B2 (en) 2014-08-12 2022-04-26 Monash University Lymph directing prodrugs
CN108138239A (zh) * 2015-07-24 2018-06-08 高丽大学校产学协力团 用于确定衰老、确定肥胖症和诊断癌症的生物标志物和使用其的诊断试剂盒
WO2017018735A1 (ko) * 2015-07-24 2017-02-02 고려대학교 산학협력단 노화 판별용, 비만 판별용, 암 진단용 바이오마커 및 이를 이용한 진단키트
US11738087B2 (en) 2015-09-08 2023-08-29 Monash University Lymph directing prodrugs
US10214536B2 (en) 2016-01-29 2019-02-26 The Regents Of The University Of Michigan Amlexanox analogs
WO2017197303A1 (en) * 2016-05-13 2017-11-16 University Of North Carolina At Greensboro Methods and compositions for the inhibition of quorum sensing in bacterial infections
WO2018049019A1 (en) * 2016-09-07 2018-03-15 Temple University - Of The Commonwealth System Of Higher Education Compositions and methods for treatment of insulin resistance
CN110139644A (zh) * 2016-09-07 2019-08-16 坦普尔大学 用于治疗胰岛素抵抗的组合物和方法
US10729670B2 (en) 2016-09-07 2020-08-04 Temple University—Of The Commonwealth Systems Of Higher Education Compositions and methods for treatment of insulin resistance
AU2017324510B2 (en) * 2016-09-07 2023-08-31 Temple University - Of The Commonwealth System Of Higher Education Compositions and methods for treatment of insulin resistance
US11596615B2 (en) 2016-09-07 2023-03-07 Temple University—Of the Commonwealth System of Higher Education Compositions and methods for treatment of insulin resistance
CN110475857A (zh) * 2017-01-05 2019-11-19 韩国生命工学研究院 表达抗-可替宁嵌合抗原受体的天然杀伤细胞
US11883497B2 (en) 2017-08-29 2024-01-30 Puretech Lyt, Inc. Lymphatic system-directing lipid prodrugs
US12178875B2 (en) 2017-08-29 2024-12-31 Seaport Therapeutics, Inc. Lymphatic system-directing lipid prodrugs
WO2021051172A1 (en) * 2019-09-19 2021-03-25 Monash University Lipid prodrugs of celecoxib and uses thereof
KR20210112647A (ko) * 2020-03-05 2021-09-15 주식회사 메타이뮨텍 오에노테인 b 유사체를 유효성분으로 포함하는 체중 감량용 조성물
KR102376806B1 (ko) * 2020-03-05 2022-03-21 주식회사 메타이뮨텍 오에노테인 b 유사체를 유효성분으로 포함하는 체중 감량용 조성물
WO2021177660A1 (ko) * 2020-03-05 2021-09-10 주식회사 메타이뮨텍 오에노테인 b 유사체를 유효성분으로 포함하는 체중 감량용 조성물
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